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  • Inopportunely normal aging brings about decreases in frontal


    Inopportunely, normal aging brings about decreases in frontal D1 receptor densities and a gradual decline in postsynaptic markers of dopamine in striatal, neocortical, and limbic areas of the Cilostazol (Bäckman et al., 2006, de Keyser et al., 1990, Karrer et al., 2017, Suhara et al., 1991, Wang et al., 1998). Dopaminergic cell bodies in the substantia nigra are also negatively influenced by age, with a 3% reduction per decade (Bäckman et al., 2006, Fearnley and Lees, 1991). Because heritability of cognitive function (McClearn et al., 1997, Raz and Lustig, 2014) and brain structural properties (Kochunov et al., 2015) increase with age, and because it is also quite likely that gene expression differs with age across individuals (because of epigenetic factors), there may be important gene x age interactions on the effect of the gene on brain and cognitive function. The resource modulation hypothesis (Lindenberger et al., 2008) postulates that the effects of genes on cognitive performance are magnified in older adults because the neural systems are now degraded; however, this association is nonlinear as the neural system becomes further degraded, and the gene effects begin to diminish. Given that the prefrontal circuitry is widely believed to support executive functions and because aging is associated with DA reduction, the role of DA and the COMT ValMet polymorphism have been examined for their effects on cognitive aging (Barnett et al., 2007, Papenberg et al., 2015, Raz et al., 2009, Witte and Flöel, 2012). Previous research indicates that the D1 receptor system plays a role in executive function and working memory, with lower DA receptor density and binding being associated with poorer performance on various cognitive tasks (Ito et al., 2008, Karlsson et al., 2009, McNab et al., 2009, Müller et al., 1998, Rieckmann et al., 2011, Salami et al., 2018, Wang et al., 1998). Studies examining the COMT ValMet polymorphism in healthy adults demonstrated that individuals with the lower enzymatic activity Met allele(s) evidence better cognitive performance compared to their Val counterparts, likely because of the greater synaptic DA in the Met carriers (Barnett et al., 2007, Caldú et al., 2007, Egan et al., 2001, Joober et al., 2002, Malhotra et al., 2002, Raz et al., 2009, Rosa et al., 2004, Witte and Flöel, 2012), but these effects are expected to be small (Barnett et al., 2008). In addition, according to the resource modulation hypothesis, COMT genotype may modulate the effects of age on cognitive performance (Li et al., 2010, Lindenberger et al., 2008, Nagel et al., 2008, Papenberg et al., 2015). Given these considerations, the present study aimed to take advantage of the natural Mendelian randomization of biological characteristics, here dopamine availability Cilostazol at D1 receptors, that influence the aging process, in situations that cannot be easily or ethically experimentally randomized or manipulated (Mattay et al., 2008, Raz and Lustig, 2014). We do so by examining the effects of a candidate gene polymorphism, COMT ValMet, on cortical thickness in regions receiving projections from the mesocortical dopaminergic pathways. We chose to investigate cortical thickness as our measure of brain morphometry because it is a reasonably specific measure of brain structure (a proxy for laminar thickness) compared to tissue volume and because cortical thickness studies in rodents (Sannino et al., 2015) and children (Shaw et al., 2009) suggest that this metric of morphometry may be particularly influenced by COMT. Indeed, Cerasa et al. (2010) found small, local, but promising effects of COMT on thickness in a lifespan sample. We also investigate whether this association is age-dependent (i.e., age x gene interactions on regional thickness) and whether these COMT-brain associations have cognitive consequences. Specifically, we hypothesize that (1) regional cortical thickness of frontal, parietal, and cingulate cortex will be reduced in individuals genetically predisposed to lower dopamine availability (COMT Val carriers), (2) that COMT-thickness associations may magnify with increasing age, and (3) that COMT-related reductions in cortical thickness will be associated with poorer performance on executive function tasks.